Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.

Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA decay pathway with roles in cellular stress responses, differentiation, and viral defense. It functions in both quality control and post-transcriptional regulation of gene expression. NMD has also emerged as a modulator of cancer progression, although available evidence supports both a tumor suppressor and a pro-tumorigenic role, depending on the model. To further investigate the role of NMD in cancer, we knocked out the NMD factor SMG7 in the HT1080 human fibrosarcoma cell line, resulting in suppression of NMD function. We then compared the oncogenic properties of the parental cell line, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. We also tested the effect of a drug inhibiting the NMD factor SMG1 to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays and a mouse xenograft tumor model, we showed that suppression of NMD function severely compromises the oncogenic phenotype. Molecular pathway analysis revealed that NMD suppression strongly reduces matrix metalloprotease 9 (MMP9) expression and that MMP9 re-expression partially rescues the oncogenic phenotype. Since MMP9 promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation may contribute to the reduced tumorigenicity of NMD-suppressed cells. Collectively, our results highlight the potential value of NMD inhibition as a therapeutic approach

Sun Exposure Guidelines and Serum Vitamin D Status in Denmark: The StatusD Study

Little is known on how vitamin D status is affected by adherence to UVB-limiting sun exposure guidelines. Our aim was to investigate the relationship between adherence to the Danish sun exposure guidelines and vitamin D status. In total, 3194 Danes (2625 adults, 569 children) were recruited among the general population, and more than 92% had blood samples taken both autumn and spring. Using linear regression, we associated serum vitamin D concentrations to questionnaire responses on: seeking shade, wearing a sunhat, wearing protective clothing or using sunscreen. The odds ratio (OR) of either low (<25 or 50 nmol/L) or adequate/high (≥50 nmol/L) vitamin D status was examined using logistic regression. For adults, those who always sought shade or wore protective clothing compared to those who did not had lower levels of vitamin D (autumn concentrations for shade: 7.2 nmol/L lower (−11.0–−3.6 nmol/L); for protective clothing: 9.9 nmol/L lower (−13.6–−6.2 nmol/L). Adherence to all four guidelines was also associated with lower vitamin D concentrations (autumn: 9.7 nmol/L lower (−14.3–−5.1 nmol/L). Use of sunscreen was associated with adequate vitamin D status, as those who always sought shade compared to those who did not had an OR (95% CI) of 1.68 (1.25–2.35) of having ≥50 nmol/L during both spring and autumn. No associations were found with wearing a sunhat, and there were no clear associations for children. In conclusion, adherence to the sun exposure guidelines on shade and protective clothing was associated with lower vitamin D status among Danish adults, but not children

Vitamin D Status and Seasonal Variation among Danish Children and Adults: A Descriptive Study

The aim of the present study was to describe vitamin D status and seasonal variation in the general Danish population. In this study, 3092 persons aged 2 to 69 years (2565 adults, 527 children) had blood drawn twice (spring and autumn) between 2012 and 2014. A sub-sample of participants had blood samples taken monthly over a year. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured by liquid chromatography mass spectrometry, and information on supplement use was assessed from questionnaires. Seasonal variations in 25(OH)D concentrations were evaluated graphically and descriptively, and status according to age, sex, and supplement use was described. It was found that 86% of both adults and children were vitamin D-sufficient in either spring and or/autumn; however, many had a spring concentration below 50 nmol/L. A wide range of 25(OH)D concentrations were found in spring and autumn, with very low and very high values in both seasons. Among adults, women in general had higher median 25(OH)D concentrations than men. Furthermore, vitamin D supplement use was substantial and affected the median concentrations markedly, more so during spring than autumn. Seasonal variation was thus found to be substantial, and bi-seasonal measurements are vital in order to capture the sizable fluctuations in vitamin D status in this Nordic population

Deep Learning-based Modeling for Preclinical Drug Safety Assessment.

In drug development, assessing the toxicity of candidate compounds is crucial for successfully transitioning from preclinical research to early-stage clinical trials. Drug safety is typically assessed using animal models with a manual histopathological examination of tissue sections to characterize the dose-response relationship of the compound - a time-intensive process prone to inter-observer variability and predominantly involving tedious review of cases without abnormalities. Artificial intelligence (AI) methods in pathology hold promise to accelerate this assessment and enhance reproducibility and objectivity. Here, we introduce TRACE, a model designed for toxicologic liver histopathology assessment capable of tackling a range of diagnostic tasks across multiple scales, including situations where labeled data is limited. TRACE was trained on 15 million histopathology images extracted from 46,734 digitized tissue sections from 157 preclinical studies conducted on Rattus norvegicus. We show that TRACE can perform various downstream toxicology tasks spanning histopathological response assessment, lesion severity scoring, morphological retrieval, and automatic dose-response characterization. In an independent reader study, TRACE was evaluated alongside ten board-certified veterinary pathologists and achieved higher concordance with the consensus opinion than the average of the pathologists. Our study represents a substantial leap over existing computational models in toxicology by offering the first framework for accelerating and automating toxicological pathology assessment, promoting significant progress with faster, more consistent, and reliable diagnostic processes

La varicelle aux urgences pédiatriques d'un hôpital parisien (caractéristiques épidémiologiques sur 3 ans)

Le nombre de cas annuels de varicelle est de l'ordre de 600 000 à 700 000, 95% concernant des sujets de moins de 20 ans. Considérée comme bénigne, la varicelle est en fait à l'origine de nombreuses complications (estimée à 2%). L'hôpital Robert Debré est un hôpital parisien dont l'une des particularités est de disposer d'un service d'urgences pédiatriques pouvant accueillir 200 enfants par jour, avec des pointes à 280 l'hiver. A partir de 1293 dossiers médicaux informatisés par le progiciel URQUAL, cette étude prospective menée sur 3 ans a pour but de décrire les critères épidémiologiques des enfants amenés aux urgences pour une varicelle et de détailler plus précisément les cas ayant nécessité une hospitalisation. Pour l'hôpital Robert Debré, la varicelle représente en moyenne un passage par jour aux urgences et un peu plus d'une hospitalisation par mois. Les infections bactériennes de la peau ou des tissus mous sont les premières causes d'hospitalisation, ce qui est retrouvé dans la plupart des études internationales. Le niveau socio-économique et l'origine multi-ethnique de notre population ont probablement favorisé la survenue de ces surinfections. Le principal facteur de risque d'hospitalisation est la fièvre. Il faut donc être partiellement attentif devant un enfant qui consulte pour varicelle et qui présente une fièvre élevée ou prolongée. La varicelle représente donc un impact certain avec un nombre de consultations aux urgences et d'hospitalisation significatifs et un risque de transmission nosocomiale aux enfants fragilisés et aux professionnels de santé non immunisés. Actuellement, la varicelle est une affection qui peut être prévenue par la vaccination. Le dernier calendrier vaccinal de 2004 ne recommande qu'une vaccination ciblée. Les données récentes devraient inciter à une réflexion sur la vaccination systématique ; un vaccin combiné Rougeole-Oreillons-Rubéole-Varicelle pourrait être une voie pour régler le problème de couverture vaccinale.The annual incidence of varicella in France is about 600 000 to 700 000, 95% regarding patients under 20 years. Usually considered as benign, chickenpox can cause complications (assessed at 2%). The Robert Debré hospital is a parisian hospital with an emergency department which can receive 200 children per day. With 1293 computerized files, this prospective study for 3 years, had for aim to describe the epidemiologic features of children seen for chickenpox and to give a detailled account of the children hospitalised. For the Robert Debré hospital, varicella represents about one consultation per day in the emergency department and a little more than one hospitalisation per month. The skin infections are the first cause of hospitalisation, as it is already schown in the other international studies.The socioeconomic level and the multi-ethnic origin of our population probably were in favour of surinfections. The main risk factors for hospitalisation is the fever. We must pay attention when we see a children with varicella who presents an hight or prolonged fever. Varicella has a certain impact with an hight incidence of consultations in the emergency department, a significant number of hospitalisations which can caused a risk of nosocomial transmission to delicate children or susceptible health-care workers. Actually, chickenpox can be prevented by vaccination. The last recommandations do not a advice the universal immunisation. Recent advances should encourage a french thought about this subject ; a combinated ROR-Varicella vaccine should allow to obtain satisfactory vaccinal coverage.PARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les méningites aseptiques aux urgences pédiatriques (Intéret médico-économique de la PCR-Entérovirus)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

ANALYSE DES DELAIS D'ATTENTE EN FONCTION DE LA PATHOLOGIE DANS UN SERVICE D'URGENCES PEDIATRIQUES EN PERIODE HIVERNALE

PARIS13-BU Serge Lebovici (930082101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Méningococcémies occultes (à propos de trois cas d'enfants vus aux urgences pédiatriques au stade de fièvre isolée ayant démasqué ultérieurement une méningococcémie)

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF